Is NPHP3 p.Glu145fs (c.434_437del) pathogenic?

NPHP3 p.Glu145fs (c.434437del) is classified Pathogenic in NPHP3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-11). Ultra-rare (popmax 0.0134%, amr); Associated with NPHP3-related disorder.

What condition is associated with NPHP3 p.Glu145fs (c.434_437del)?

NPHP3 p.Glu145fs (c.434_437del) is associated with NPHP3-related disorder, renal-hepatic-pancreatic dysplasia 1, NPHP3-related Meckel-like syndrome (ClinVar).

How common is NPHP3 p.Glu145fs (c.434_437del) in the general population?

NPHP3 p.Glu145fs (c.434_437del) is ultra-rare (popmax 0.0134%, amr) (gnomAD).

NPHP3 p.Glu145fs

c.434_437del · rs763300393 · VCV195423

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, amr)

Conditions

NPHP3-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 27
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.82	GERP -0.62, phastCons 0.96
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% Admixed American · 8/59,576 alleles

Filtering AF 0.00666% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00485%

Overall 0.00518% 83/1,601,086 alleles · ultra-rare exomes 76/1,449,152 · genomes 7/151,934 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0134%	7,447
European (non-Finnish)	0.00614%	16,277
Remaining individualsnot grpmax-eligible	0.00485%	20,622

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NPHP3
Protein: p.Glu145fs
Coding: c.434_437del
MANE Select: NM_153240
dbSNP: rs763300393
Type: Microsatellite
Location: chr3:132719787 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.59 · 1 PDB

Full NPHP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: renal-hepatic-pancreatic dysplasia 1 NPHP3-related Meckel-like syndrome nephronophthisis 3 nephronophthisis

Similar variants

NPHP3 p.Ala1135fs Pathogenic ★★ same condition
NPHP3 p.Gly1275del Pathogenic/Likely pathogenic ★★ same condition
NPHP3 p.Leu365fs Pathogenic ★★ same condition
NPHP3 p.Ser611fs Pathogenic ★★ same condition
NPHP3 p.Ser960fs Pathogenic ★ same condition
NPHP3 c.3813-12TC[2] Uncertain significance ★ same condition
NPHP3 p.Glu1292del Uncertain significance ★ same condition
NPHP3 p.Glu145Gln Uncertain significance ★ same residue

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nphp3-p-glu145fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown